Pulmonary embolism results when a thrombus forms somewhere in the venous system, most commonly in the deep veins of the lower extremities, and dislodges, traveling through the right side of the heart before becoming lodged in the pulmonary arterial circulation. Pulmonary embolism causes symptoms and occasionally hemodynamic instability through several mechanisms including obstruction of pulmonary blood flow and liberation of vasoconstrictive cytokines. Thus, although deep venous thrombosis and pulmonary embolism are closely related pathophysiologically, they differ significantly in presentation and means of diagnosis.

The diagnosis of pulmonary embolism generally requires some form of imaging the results of which must be interpreted in conjunction with the clinical likelihood of the disease.

The single most important factor in evaluating a patient for suspected pulmonary embolism is determination of the clinical probability of disease as no single laboratory or imaging test can rule-in or rule-out the diagnosis.

►Important: No test done in the evaluation of a patient with suspected pulmonary embolism can be interpreted without first considering the clinical likelihood of disease.

Clinical criteria for diagnosis should include clinical probability of disease as determined by clinical gestalt or a validated clinical predication model such as the Well or Geneva Score or negative predictive models such as the PERC model. The diagnosis is confirmed in the following situations:

Figure 1.

Pulmonary Embolism Diagnosis Algorithm

A. History Part I: Pattern Recognition:

Patients with pulmonary embolism defy a "typical presentation" as many of the manifestations are non-specific and protean. The classic presentation triad of pleuritic chest pain, dyspnea and tachycardia is uncommon and non-specific. The most important aspect of the history is determining whether an alternate condition that may explain the symptoms and signs is present.

* Only symptoms and signs seen consistently in more than 50% of patients (independently)

All patients in whom pulmonary embolism is considered should have pre-test likelihood determination applied. Although clinical gestalt has been validated when used by experienced physicians, it is generally considered more reliable to use one of the validated clinical prediction tools. Many such tools exist, although the simplified wells score is one of the easiest to use.

Simplified Wells Score

Score points for each of the following clinical findings:

-Clinical signs/symptoms of DVT = 3 points

-Alternative diagnosis less likely than PE = 3 points

-Heart rate>100 beats/minute = 1.5 points

-Immobilization for more than 3 days or surgery in prior 4 weeks = 1.5 points

Additionally the PERC (Pulmonary Embolism Rule-Out Criteria) score has started to be employed to “Rule-out” PE in the emergency room setting. The PERC score is a negative scoring system in which a point is given for not meeting the criteria. A PERC score of 0 “rules-out” a PE without further testing. A PERC score of 1 or greater should be followed by a d-dimer or conclusive imaging if another scoring system evaluates the patient to be at high clinical probability of a PE. The PERC score criteria are:

Age<50

Heart Rate<100

Initial Oxygen saturation on Room Air >94 percent

No unilateral leg swelling

No hemoptysis

No surgery or trauma within 4 months

No history of VTE

No estrogen use

No point is given if the patient meets the criteria. One point is given for each criterion not met. As previously stated a score of one or greater should be pursued with further testing based on clinical prediction rules such as the Wells or other scouring systems.

B. History Part 2: Prevalence:

Most patients will have at least one risk factor for VTE. Common risk factors for pulmonary embolism include:

C. History Part 3: Competing diagnoses that can mimic Pulmonary Embolism.

Many diagnoses present in a similar fashion to PE. Among the most common are the following:

Pneumonia and sepsis

Pneumothorax

Acute coronary syndrome

Acute pericarditis

Aortic dissection

Costochondritis

Pleuritis

Differentiation of the above from pulmonary embolism is difficult and depends on how strong the diagnostic case is for the alternative diagnosis. Each of the above has salient findings that make it at least relatively likely (e.g., infiltrate on CXR for pneumonia, ECG changes and enzyme leak with ACS) and it is the lack of any of these distinctive findings that makes PE more likely.

D. Physical Examination Findings.

As with the history, many findings on physical examination may suggest the diagnosis but none establish it. In large part, the value of the physical examination in patients with suspected pulmonary embolism lies in uncovering findings that suggest an alternate diagnosis (such as unilateral absent breath sounds in pneumothorax and a pericardial friction rub in acute pericarditis).

E. What diagnostic tests should be performed?

The diagnostic approach to the patient with suspect pulmonary embolism is entirely dependent on the clinical probability of disease.

In the patient with a low clinical probability of disease (or PE "unlikely" if the Wells Score is used), the initial test should be the d-dimer. If the d-dimer is negative, the diagnosis of PE may be discounted.

If the patient has a positive d-dimer or a moderate/high clinical probability of disease (or PE "likely" by the Wells Score), then the initial test should be a CT scan of the chest under a rule-out pulmonary embolism protocol.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

There is no laboratory test that establishes the diagnosis of pulmonary embolism and there is no single test that should be done in every patient.

D-dimer:The rapid ELISA d-dimer level is very useful in excluding the diagnosis of pulmonary embolism in the proper patient population. There is recent evidence for increase value for age adjusted d-dimer (ageX10 in patients aged >50 years) over fixed cutoff (<500), being mindful of measuring units. Bedside latex agglutination assays do not have sufficiently strong test characteristics to be used for this purpose. In patients with a low clinical probability of pulmonary embolism, a negative d-dimer safely excludes the diagnosis. The test, however, should not be used in patients with a moderate or high probability of pulmonary embolism as there remains a significant chance of pulmonary embolism in these patients even with a negative d-dimer.

Arterial blood gas: Arterial blood gases are of little utility in evaluating the patient with suspected pulmonary embolism. Although many patients with pulmonary embolism have an increased alveolar-arterial oxygen gradient with a concomitant respiratory alkalosis, these findings are not specific to patients with pulmonary embolism and do little to distinguish PE from other causes of dyspnea and chest pain. They should be done only when they may help in the evaluation of other diagnostic possibilities, such as chronic obstructive pulmonary disease.

Troponin and Natriuretic Peptides: Their levels may be elevated in acute pulmonary embolism secondary to right heart strain(or Right Ventricular dysfunction) but are non-specific. An elevated level may indicate a worse prognosis but is not helpful in directing the diagnostic or therapeutic plan.

Thrombotic Risk Factor Panel: These panels are of little utility and are not necessary in most patients unless a clear indication for testing exists. Tests such as Protein C, Protein S and Antithrombin III can be affected by the VTE process or by specific medication use. Additional testing specifically to look for hereditary causes that are not affected by acute thrombotic state like Factor V leiden, Prothrombin 20210G>A and antiphospholipid syndrome, according to many recommendations, can deferred till a later point after discharge.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Chest X-ray: The majority of patients with pulmonary embolism have an abnormal chest film, although the findings are rarely caused by the embolism itself. Only 12% of patients have a normal chest film. The major utility of the chest film is in finding other causes of the patient's symptoms (i.e. an infiltrate in pneumonia or absent lung markings in pneumothorax). Hampton's Hump and Westermark's Sign are the only findings with any specificity to pulmonary embolism.

CT scan of chest under pulmonary embolism protocol (helical or spiral CT): The CT scan is the most commonly utilized imaging study in patients with suspected pulmonary embolism. It has good test characteristics (positive likelihood ratio of ~20; negative likelihood ratio of <0.10), can be completed quickly and often provides information related to other potential diagnoses (e.g., pneumonia, lung cancer). Drawbacks include exposure to ionizing radiation and the need for intravenous contrast dye, limiting utility in patients with kidney disease. It is the initial test of choice in patients with a moderate or high probability of disease and the most appropriate next test in patients with a low clinical probability of disease but a positive d-dimer assay.

Ventilation-perfusion (VQ) scan: Despite being supplanted by the CT in the evaluation of most patients with suspected PE, the VQ scan remains a viable diagnostic option. It is most often used when a patient may not receive intravenous contrast dye, specifically those patients with allergy to dye or significant kidney injury/disease. A normal chest X-ray greatly increases the likelihood of a definitive VQ scan result. It has well-characterized test characteristics and is safe, but requires substantial time to complete, is not widely available and, most importantly, its results are commonly misinterpreted by clinicians. To properly interpret the results of a VQ scan, one must combine the pre-test clinical probability and the VQ scan result to determine the post-test probability of pulmonary embolism.

Lower extremity duplex ultrasonography: Lower extremity ultrasonography is a second-line test in patients with suspected pulmonary embolism. The rationale for use rests on the supposition that a positive scan for deep venous thrombosis indicates the clinical findings are secondary to concomitant pulmonary embolism (as occurs at least 50% of the time with deep venous thrombosis). It, however, has limited utility in ruling out pulmonary embolism (negative likelihood ratio of ~0.73) except when used in serial fashion in patients with good cardiopulmonary reserve.

Lower extremity ultrasonography should not be used as a first-line test except in those circumstances where a CT may not be performed and VQ scanning is not available (such as in patients with kidney disease in institutions where a VQ scan is unobtainable). It is useful as a second-line test in those patients in whom diagnostic uncertainty remains after the CT scan (i.e. high clinical probability but a negative CT) or VQ scan.

Pulmonary angiography: Although pulmonary angiography is the gold standard test for pulmonary embolism, it has substantial drawbacks including its invasive nature, the need for intravenous contrast dye and limited availability. Use is generally limited to those situations where diagnostic uncertainty remains despite extensive evaluation with other methods of testing and the establishment of a definitive diagnosis is critical.

Echocardiography: Echocardiography is a poor first-line test for pulmonary embolism. Its use is limited to help determine prognosis as a dilated right ventricle portends increased mortality, although the effect of this information on treatment options is limited.

Magnetic resonance imaging (MRI): Because of issues relating to technical quality of study, difficulty in interpretation and accessibility, MRI is rarely used in the evaluation of patients with suspected pulmonary embolism. Although it was initially heralded as a potentially useful test in patients with kidney disease, the emergence of nephrogenic systemic fibrosis has further limited its utility in this situation.

Interpreting a VQ scan result

A VQ scan result can only be interpreted in light of the predetermined clinical probability. Given that the studies with VQ scan were completed prior to the Wells Score, clinical gestalt is used and patients are stratified into low, moderate and high probabilities of PE based on the clinical findings. The VQ scan result is reported out as normal, low probability, indeterminate and high probability.

A high probability scan result with a high or moderate clinical probability secures the diagnosis of PE

A high probability scan result with a low clinical probability, means PE is likely but further testing may be considered.

An indeterminate scan result means anywhere from a 66% (high clinical probabilty) to 15% (low clinical probability) chance of PE and more testing is indicated in most patients.

A low probability scan result with a low clinical probability rules out PE in practicality.

A low probability scan result with a moderate or high clinical probability yields a 15-40% chance of PE, necessitating more testing.

A normal scan result excludes the diagnosis regardless of clinical probability.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

All tests must be ordered after specific consideration of the clinical probability of disease in the individual patient. In patients with a moderate or high probability of disease, a d-dimer level should not be ordered. Similarly, a CT scan may be avoided in patients with a low clinical probability of disease if a d-dimer assay is negative.

III. Default Management.

Management of pulmonary embolism in all patients includes consideration of:

1) Thrombolytic therapy

2) Immediate systemic anticoagulation

3) Inferior venacaval interruption

A. Immediate management.

1) Thrombolytic therapy: Thrombolysis has a limited role in the treatment of pulmonary embolism but may be life saving in select patients. Given in the form of intravenous tPA, thrombolysis should be administered to patients without contraindications who are in shock secondary to pulmonary embolism. Although other indications for thrombolysis including right ventricular strain on echocardiography and elevated troponin levels have been suggested, there is no clear data to demonstrate it improves outcomes in these situations.

2) Immediate anticoagulation: Unless undergoing thrombolytic therapy, all patients with confirmed pulmonary embolism and without strong contraindications should be immediately anticoagulated. In addition, patients with a moderate to high likelihood of pulmonary embolism without a high risk of bleeding should be anticoagulated while undergoing testing for PE even before the diagnosis is confirmed.

Standard approach:

For stable and non-massive PE the latest version of evidence based guideline for treatment of venous thromboembolism (VTE) by American College of Chest Physicians (ACCP), published in the journal Chest, states the use of Non-Vitamin K Oral Anticoagulants/ Direct Oral Anticoagulants (NOAC/DOAC) should be considered as the first choice for long term anticoagulation in non-cancer related VTE (Grade 2B). The agents orally administered -direct thrombin inhibitor such as dabigatran and the Factor Xa (FXa) inhibitors such as rivaroxaban, apixaban or edoxaban.

Among FXa inhibitors rivaroxaban and apixaban does not require initial bridging with parental anticoagulation (e.g., Heparin drip, Enoxaparin) but both edoxaban and dabigatran can only be initiated after 5-10 days of parental anticoagulation.

It is prudent to note that those with massive PE and hemodynamic instability presenting with shock or severe hypotension who are candidates for thrombolytic therapy and/or embolectomy were not included in NOAC trials. These patients, therefore, may not be considered appropriate candidates for initial treatment with NOACs given lack of data at the present. However, upon favorable clinical evolution, they can be considered for the continued treatment and for long-term secondary prevention.

Reversal of Dabigatran with Idarucizumab was approved by FDA in October, 2015. Currently the reversal agent for Factor Xa inhibitors are in various stages of development but none are approved for use in the US at this time.

For Massive or “High Risk” PE, patients should still be started on heparin if there is a concern that thrombolysis will be needed. If no concern for need for thrombolysis and the patient is hemodynamically stable without evidence of acute right heart strain a low-molecular heparin can be considered.

For “intermediate risk” (submassive) or “low-risk” PE where a NOAC/DOAC is not chosen as the treatment low molecular weight heparins are likely modestly superior to unfractionated heparin for pulmonary embolism. Administer subcutaneously and dosed by patient weight, they result in reliable and immediate anticoagulation. They, however, are difficult to use in markedly obese patients and are contraindicated in advanced kidney disease (CrCl<30ml/min). As previously stated, there is limited experience in patients with marginal hemodynamics as these patients were specifically excluded from the trials of low-molecular weight heparin in PE.

Intravenous unfractionated heparin begun as a bolus and followed by a continuous infusion is also effective. A weight-based protocol should be used and frequent monitoring of the activated partial thromboplastin time (aPTT) is required. Failure to achieve a therapeutic aPTT (1.5 times the control value) within 24-hours is associated with worse clinical outcomes and close attention must be paid to ensuring anticoagulation is adequate. Conversely supra-therapeutic anticoagulation in the first several days of therapy is not clearly associated with an increased risk of bleeding. Unfractionated heparin may also be administered via intermittent subcutaneous injection, although clinical experience with this approach is limited.

Because of superior efficacy, low-molecular weight heparin should be used in most patients with pulmonary embolism who are not started on a NOAC/DOAC. Unfractionated heparin, however, is preferred in the following settings:

-a surgical procedure is anticipated in the short-term,

-the patient is thought to be at very high risk of bleeding in the short-term,

-morbid obesity,

-significant renal dysfunction (CrCL<30ml/min), and

-Hemodynamic instability.

Once systemically anticoagulated with heparin, for patients whom the choice has been made to start on warfarin, a standard warfarin dosing algorithm should guide initiation of therapy. Heparin therapy should be continued through at least the first 4-5 days of warfarin therapy even if the INR becomes therapeutic more quickly. Once the INR has been in the therapeutic range for at least 2 consecutive days, the heparin may be discontinued. Warfarin therapy causes a rapid depletion of coagulant factor VII (shortest half life, 4-6 hrs) which results in elevated INR, although most of the true anticoagulant effect of warfarin comes from the depletion of other clotting factors such as Factors II,IX and X which take longer to drop. Discontinuing the heparin coverage sooner, even with a therapeutic INR, may result in adverse events.

Special consideration for Anticoagulant Monitoring while on unfractionated heparin (UFH):

In patients with history of Positive Lupus anticoagulant (LA) and those requiring large daily doses of heparin, use of PTT may not be the accurate assay to measure the anticoagulant effect of the heparin. LA is the anti phospholipid autoantibody that has been associated with a thrombotic tendency and spuriously elevated PTT in vitro. In such scenarios, Anti -Xa (Heparin) level should be measured which provides a direct measure of heparin activity.

Other anticoagulants

Betrixaban (bevyxxa): Up until very recently there was no options for high risk hospitalized patient with moderate to severe restricted mobility due to pneumonia, stroke, heart failure to prevent VTE after discharge. Guidelines recommend the use of low-dose parenteral anticoagulants for only 6 to 14 days but advise against extended-duration thromboprophylaxis after hospital discharge. However, the risk remains markedly increased for the first month after hospital discharge. On June 23, 2017, FDA approved betrixaban (BEVYXXA), an oral, direct factor Xa inhibitor, for the prophylaxis of VTE in adult hospitalized patients for an acute medical illness who are at high risk for up to 35 to 42 days after hospital discharge. Efficacy was shown in randomized, double-blind, multinational trial APEX (NCT01583218).

Fondaparinux: This agent has been shown to be as effective as intravenous unfractionated heparin in the treatment of acute pulmonary embolism with similar bleeding rates and is FDA-approved for this indication. Given the relatively limited experience, however, its use is reserved for limited situations such as prior heparin-induced thrombocytopenia.

Direct thrombin inhibitors - intravenous (argatroban, bivalarudin): Although the intravenous direct thrombin inhibitors argatroban and bivalirudin result in immediate and reliable anticoagulation, there is little data on their use for treatment of pulmonary embolism.

3) Vena caval interruption: Although at times employed, there is limited data to support the use of vena caval filters in acute pulmonary embolism. They are most commonly used to prevent recurrent events in patients with established pulmonary embolism who have significant contraindications to anticoagulation such as active bleeding. They are also used for other indications including sub-massive pulmonary embolism and significant concomitant significant lower extremity deep venous thrombosis, although there is no data to support this approach.

Of note, although IVC filters do decrease the risk of pulmonary embolism in the short-term, they are associated with a high risk of long-term deep venous thrombosis. As such, retrievable filters may be placed although there is little data regarding the utility of this approach. In 2010, study done by Nicholson and colleagues revealed high fracture rate of IVC filters. Evidence suggests that the longer the filter is in place the higher the chance of fracture. Most retrievable filters are never retrieved, despite FDA warnings.

D-dimer testing and thrombin generation after completion of therapy may help stratify the risk of recurrent disease, but more data is necessary before this approach can be recommended.

E. Common Pitfalls and Side Effects of Management.

If you choose to use a VKA for long term therapy; as the patient is transitioned to warfarin, heparin therapy should be continued for at least 4-5 days and until the INR is in the therapeutic range for at least 2 consecutive days. Warfarin therapy causes a rapid depletion of coagulation factor VII, which results in elevated INR although most of the true anticoagulant effect of warfarin comes from the depletion of other clotting factors, which take longer to drop.

IV. Management with Co-Morbidities.

N/A

A. Renal Insufficiency.

The management of pulmonary embolism is significantly altered in the presence of significant renal disease. The non-vitamin K oral anticoagulants have differencing properties in various levels of renal insufficiency. Their use can be guided by prescribing outlines depending on a person’s renal function. Low molecular weight heparin cannot be used with a CrCl <30ml/min necessitating use of unfractionated intravenous heparin when these agents are needed.

B. Liver Insufficiency.

Titration of warfarin therapy in patients with severe liver disease and an elevated INR is difficult and the baseline INR must be kept in mind when assessing the adequacy of anticoagulation. Most patients with an elevated INR secondary to liver disease are poor candidates for systemic anticoagulation.

Trials of NOAC/DOACs excluded patients with cirrhosis and there is no current guidance on their use in severe liver disease. While data is currently emerging and this topic will likely be altered in the next few years.

C. Systolic and Diastolic Heart Failure.

No change in standard management.

D. Coronary Artery Disease or Peripheral Vascular Disease.

No change in standard management.

E. Diabetes or other Endocrine issues.

No change in standard management.

F. Malignancy.

Patients with malignancy and pulmonary embolism present a unique problem as in many cases the thrombosis is driven by the presence of malignancy (particularly adenocarcinomas). Malignancy-associated pulmonary embolism may be "warfarin-resistant" and heparin is effective in this situation. Long-term anticoagulation with low molecular weight heparin is currently the recommended treatment as long as the patient is accepting of the need for daily injections, if not other options may need to be considered. Anticoagulation should be continued lifelong unless the malignancy is cured.

G. Immunosuppression (HIV, chronic steroids, etc).

No change in standard management.

H. Primary Lung Disease (COPD, Asthma, ILD).

No change in standard management.

I. Gastrointestinal or Nutrition Issues.

In patients with active gastrointestinal bleeding, anticoagulation is contraindicated and IVC filter placement may be necessary. Chronic gastrointestinal blood loss is a relative contraindication to anticoagulation and therapy must be individualized to the patient.

J. Hematologic or Coagulation Issues.

K. Dementia or Psychiatric Illness/Treatment.

Long-term anticoagulation may be difficult in patients with dementia secondary to issues with medical adherence and fall risk. Therapy decisions must be individualized although at least short-term anticoagulation is usually indicated.

B. Anticipated Length of Stay.

If on low molecular weight heparin, length-of-stay may be 2-3 days if close interval follow-up of INR and home administration of heparin can be arranged.

C. When is the Patient Ready for Discharge?

Criteria for discharge include:

-Normal hemodynamics and lack of respiratory distress

-Adequate oxygenation on room air or low flow oxygen

-Solid plan for follow-up of anticoagulation status

-If on unfractionated heparin, INR greater than 2.0 for 2 consecutive days AND at least 4-5 days of heparin/warfarin overlap.

D. Arranging for Clinic Follow-up.

As most patients are on a newer oral anticoagulant which does not require monitoring lab data, follow up should be arranged within a reasonable time frame (usually one within a week) to check on symptoms and for side effects of bleeding.

For those on older agents, plans for follow-up of anticoagulation status as an outpatient is CRITICAL and includes:

-If on warfarin, repeat INR in 1-3 days (depending on stability of INR and warfarin dose over last 3 days of hospitalization)

-If on low-molecular weight heparin, daily INR and clear communication to physician assuming care of when discontinuation of heparin is appropriate

-Communication of warfarin doses and resultant INRs to the physician assuming care of the patient

1. When should clinic follow up be arranged and with whom.

General Medical Clinical follow-up within one week is appropriate with most patients. This schedule must be accelerated if the need for active management of anticoagulation status (i.e. monitoring of INR and adjustment of warfarin dosing/discontinuation of heparin bridge therapy) is anticipated.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

None

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

Follow-up INR if on warfarin.

Platelet count may be necessary if on heparin.

E. Placement Considerations.

None specific to pulmonary embolism.

F. Prognosis and Patient Counselling.

15% mortality rate untreated.

Drug-food interaction discussion/education is critical in patient being discharged on warfarin.

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Ensure close follow-up of anticoagulation status if not on a DOAC (INR and warfarin dosing). According to recent study comparing heparin with warfarin in treating acute venous thromboembolism in patients with active cancer, the mean time in the INR therapeutic range (TTR) was only 47%.This highlights further the importance of closely monitoring and keeping therapeutic INR.

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